Processing properties of active ingredient particles, for example their bulk density, wettability, pourability, stability, solubility properties etc., depend on the particle size and quite substantially on the particle size distribution. To achieve as rapid a release as possible from dosage forms, poorly soluble active ingredients are produced with as finely particulate a form as possible. On the other hand, in a retard form in which the release behavior is controlled via the particle size, generally a coarser grain size which controls the dissolution of the active ingredient particles within the desired time window is required.
To achieve good processing properties, the particle size distribution should be as narrowly limited as possible and be reproducibly generated. Also, for reasons of processability or stability of active ingredients, there is a need to produce active ingredients with a coarser, but defined and narrow, particle size distribution, wherein it is desirable that the particle size distribution is achieved directly by crystallization if at all possible without subsequent process steps such as sieving and grinding.
Grinding devices, such as, for example, rotor/stator devices, can be used for the production of fine-grained crystal particles and controlled influencing of the particle size of active ingredients.
In “Generation of fine Pharmaceutical Particles via Controlled Secondary Nucleation under High Shear Environment during Crystallization”, Organic Process Research & Development 2007, 11, pp. 699-703, Kamahara et al. describe precipitation crystallization in a solvent-antisolvent system with the aim of achieving a strong secondary nucleation and thus as fine a grain size as possible (average particle size 8-10 μm) through high supersaturations in the shear zone of the dispersion unit. As the product suspension is circulated via crystallizer and rotor/stator, unsteady conditions with regard to concentration and supersaturation obtain if there is constant dosage of the active ingredient solution. With batch sizes of 3-20 kg, as are customary in the production of active ingredients, larger systems are generally required.
A rotor/stator grinding device in connection with a precipitation reaction for producing as fine-grained particles as possible is also described in WO 03/033097 A2. Solution and precipitant are continuously fed into the rotor/stator unit via separate feed lines and a high nucleation rate and thus a limitation of crystal growth is achieved in the shear zone of the dispersing unit.
The above-described methods are suitable for obtaining the finest possible grain sizes. However, the targeted production of coarser grain sizes in the range of average particle diameters of more than 10 μm, in particular of more than 20 μm is problematic with these precipitation reactions in the shear zone of the dispersant. Furthermore, bimodal grain sizes with high proportion of fine grains are produced by superimposing nucleation and grinding effects. In addition, the secondary nucleation rate and thus ultimately the grain size achieved depends on a large number of factors and thus harbors risks with regard to process monitoring and reproducibility.
A general problem during crystallization using wet-grinding devices, such as, e.g. rotor/stator systems, is the enormous input of dissipation heat, to which is generally added the heat of the hot active ingredient solution. As solubility is normally temperature-dependent, this heat must effectively be removed again from the system. This requires correspondingly large cooling surfaces. Due to the supersaturation naturally forming over these surfaces, these tend to become progressively encrusted (fouling). This leads to disruptions in the desired grain size by coarse particles of these crusts, blockages in the transport lines and a progressive deterioration of the heat transfer. The smaller the system, the more serious becomes the problem of heat removal and the fouling effects. A continuous operation in as small as possible and thus a low-cost system in which a stationary regime is to be maintained over an extended period of time for producing a defined grain size is not possible with these methods and systems.
In WO 03/091272 A1 it is described that, through subsequent treatment of a suspension of fine primary particles which has been obtained via crystallization with simultaneous wet grinding, a targeted and reproducible grain coarsening was able to be achieved by means of repeated partial dissolution and recrystallization through corresponding temperature profiles. Unlike the method of the above-mentioned WO 03/033097 A2, here the desired particle size distribution is not achieved predominantly by secondary nucleation, but by a better-controllable, gradual crystal growth process. However, it is disadvantageous that this is possible only via additional process steps and on an industrial scale, and only when operating in batches with correspondingly large and cost-intensive equipment. Furthermore, it is disadvantageous that crystal growth can be superimposed by the formation of agglomerates in the following tempering phase.